The number of elderly people (aged 65 and older) in the U.S. will be more than doubled, from 40.3 million in 2010 to 88.5 million in 2050. This rapid growth of the older population dramatically increases the incidence of chronic and degenerative diseases, and presents a grand challenge for public health. To tackle this challenge, our research aims to identify bioactive nutrient compounds that promote organismal longevity and fitness through modulating microbiota-host interactions, and to further characterize their underlying regulatory mechanisms. The microbiota is a collection of diverse species of microorganisms that reside in the host, and its homeostasis is strongly associated with host health and is tightly regulated by both dietary and genetic factors. Diet-driven microbiota compositional changes have been linked to health improvement among the elderly, however identification and validation of specific longevity-promoting bioactive dietary factors remain technically challenging in mammalian systems. During our preliminary studies in Caenorhabditis elegans, we identified a longevity-promoting polysaccharide, colanic acid (CA), which is secreted from bacteria and functions as a prebiotic to improve host mitochondrial dynamics. Our studies further revealed that CA promotes longevity in evolutionarily distant host organisms and is effective in diverse microbial environments. These studies suggest CA as a novel bioactive nutrient compound to improve microbiota homeostasis and to promote host metabolic health and fitness. This proposal seeks to dissect the prebiotic function of CA in the regulation of host longevity through the following specific aims: 1) Elucidate CA-mediated microbial factors that regulate host longevity; 2) Reveal the molecular mechanisms by which CA improves host longevity. 3) Assess the conserved role of CA in promoting host health and longevity in mammals. In these studies, we will apply multidisciplinary approaches and take advantages of powerful prokaryotic, invertebrate and vertebrate model systems. We have established unique collaborations with scientists in diverse areas. Successful accomplishment of the proposed studies will provide a new strategy of prebiotic therapies to improve the quality of later life, an will have significant impacts on research in the fields of nutritional science and aging biology.